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  • American Society of Hematology  (29)
  • Oxford University Press  (6)
  • Paleontological Society
  • Nature Publishing Group (NPG)
  • American Chemical Society (ACS)
  • 2010-2014  (38)
  • 2010  (38)
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  • 1
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    The landscape of somatic copy-number alteration across human cancers (2010)
    Nature Publishing Group (NPG)
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    Publikationsdatum: 2010-02-19
    Beschreibung: A powerful way to discover key genes with causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here we present high-resolution analyses of somatic copy-number alterations (SCNAs) from 3,131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across several cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-kappaBeta pathway. We show that cancer cells containing amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend on the expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in several cancer types.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2826709/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2826709/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Beroukhim, Rameen -- Mermel, Craig H -- Porter, Dale -- Wei, Guo -- Raychaudhuri, Soumya -- Donovan, Jerry -- Barretina, Jordi -- Boehm, Jesse S -- Dobson, Jennifer -- Urashima, Mitsuyoshi -- Mc Henry, Kevin T -- Pinchback, Reid M -- Ligon, Azra H -- Cho, Yoon-Jae -- Haery, Leila -- Greulich, Heidi -- Reich, Michael -- Winckler, Wendy -- Lawrence, Michael S -- Weir, Barbara A -- Tanaka, Kumiko E -- Chiang, Derek Y -- Bass, Adam J -- Loo, Alice -- Hoffman, Carter -- Prensner, John -- Liefeld, Ted -- Gao, Qing -- Yecies, Derek -- Signoretti, Sabina -- Maher, Elizabeth -- Kaye, Frederic J -- Sasaki, Hidefumi -- Tepper, Joel E -- Fletcher, Jonathan A -- Tabernero, Josep -- Baselga, Jose -- Tsao, Ming-Sound -- Demichelis, Francesca -- Rubin, Mark A -- Janne, Pasi A -- Daly, Mark J -- Nucera, Carmelo -- Levine, Ross L -- Ebert, Benjamin L -- Gabriel, Stacey -- Rustgi, Anil K -- Antonescu, Cristina R -- Ladanyi, Marc -- Letai, Anthony -- Garraway, Levi A -- Loda, Massimo -- Beer, David G -- True, Lawrence D -- Okamoto, Aikou -- Pomeroy, Scott L -- Singer, Samuel -- Golub, Todd R -- Lander, Eric S -- Getz, Gad -- Sellers, William R -- Meyerson, Matthew -- K08 AR055688/AR/NIAMS NIH HHS/ -- K08 AR055688-03/AR/NIAMS NIH HHS/ -- K08 AR055688-04/AR/NIAMS NIH HHS/ -- K08 CA122833/CA/NCI NIH HHS/ -- K08 CA122833-01A1/CA/NCI NIH HHS/ -- K08 CA122833-02/CA/NCI NIH HHS/ -- K08 CA122833-03/CA/NCI NIH HHS/ -- K08 CA134931/CA/NCI NIH HHS/ -- K08CA122833/CA/NCI NIH HHS/ -- P01CA 098101/CA/NCI NIH HHS/ -- P01CA085859/CA/NCI NIH HHS/ -- P50CA90578/CA/NCI NIH HHS/ -- R01 CA109038/CA/NCI NIH HHS/ -- R01 GM074024/GM/NIGMS NIH HHS/ -- R01CA109038/CA/NCI NIH HHS/ -- R01CA109467/CA/NCI NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- U24 CA126546/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Feb 18;463(7283):899-905. doi: 10.1038/nature08822.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Program and Medical and Population Genetics Group, The Broad Institute of M.I.T. and Harvard, 7 Cambridge Center.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20164920" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Apoptosis/genetics ; Cell Line, Tumor ; Cell Survival/genetics ; DNA Copy Number Variations/*genetics ; Gene Amplification/genetics ; Gene Dosage/*genetics ; Genomics ; Humans ; Multigene Family/genetics ; Myeloid Cell Leukemia Sequence 1 Protein ; Neoplasms/classification/*genetics/pathology ; Proto-Oncogene Proteins c-bcl-2/genetics ; Signal Transduction ; bcl-X Protein/genetics
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Nature Publishing Group (NPG)
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    The Rubisco enzyme and agricultural productivity (2010)
    Nature Publishing Group (NPG)
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    Publikationsdatum: 2010-02-19
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Porter, John R -- Wollenweber, Bernd -- England -- Nature. 2010 Feb 18;463(7283):876. doi: 10.1038/463876b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20164901" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Agriculture/*methods ; Crops, Agricultural/genetics/*growth & development/metabolism ; *Food Supply/statistics & numerical data ; Food, Genetically Modified ; *Genetic Engineering ; Ribulose-Bisphosphate Carboxylase/genetics/*metabolism
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Nature Publishing Group (NPG)
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  • 3
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    Long-Term Safety and Efficacy of Deferasirox (Exjade®) In Transfused Patients with Sickle Cell Disease Treated for up to 5 Years (2010)
    American Society of Hematology
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    Publikationsdatum: 2010-11-19
    Beschreibung: Abstract 845 Background: Transfusion therapy can effectively treat many complications associated with sickle cell disease (SCD), but iron overload will develop without iron chelation therapy. Despite long-term transfusion requirements, long-term data for iron chelation in SCD are limited. The oral iron chelator, deferasirox, effectively reduced iron burden in SCD patients aged ≥2 years during 1 year of treatment (Vichinsky et al. Br J Haematol 2007). This 5-year follow-up is the first report of long-term deferasirox treatment in SCD patients. Methods: Eligible patients that completed the 1-year core study (randomized to deferasirox [deferasirox cohort] or deferoxamine [crossover cohort]) entered the 4- year extension. All received deferasirox while continuing their regular transfusion regimen. Deferasirox dose in the extension was initially based on serum ferritin (SF) trends in the core study (deferasirox cohort) or transfusion requirements (crossover cohort). Dose adjustments were based on monthly SF and safety assessments (investigator-reported adverse events [AEs] and centrally processed lab parameters). Growth and sexual development (Tanner staging) were assessed annually. Results: Of the patients in the deferasirox (n=132) and crossover (n=53) cohorts that received ’1 deferasirox dose during the core or extension, 43 (33%) and 19 (36%) patients, respectively, completed the extension. Reasons for discontinuation included withdrawal of consent (n=44, 23.8%), loss to follow-up (n=17, 9.2%) and AEs (n=14, 7.6%). Three deaths occurred, all in the extension (intraventricular hemorrhage, n=2; intracranial bleed post liver transplantation, n=1); none considered by investigators to be deferasirox-related. Mean dose during the study was 18.7 ± 6.5 and 21.2 ± 5.3 mg/kg/day in the deferasirox and crossover cohorts, respectively. Investigator-assessed drug-related AEs (≥5% overall) included nausea (14.6%), diarrhea (10.8%), increased blood creatinine (5.9%) and vomiting (5.4%). Generally, these AEs were manageable and transient, and decreased in frequency over time. Serious AEs were reported in 70.8% of patients overall and were mostly related to the underlying disease. Serious investigator-assessed drug-related AEs were reported in 8 patients (6.1%) in the deferasirox cohort and 1 patient (1.9%) in the crossover cohort. In the deferasirox and crossover cohorts respectively, 9 (6.8%) patients and 1 (1.9%) patient had 2 consecutive serum creatinine level increases 〉33% above baseline and 〉upper limit of normal (ULN). Median creatinine clearance remained stable within normal range throughout the study. One patient from each cohort had alanine aminotransferase (ALT) 〉10 × ULN on 2 consecutive visits; both had ALT values ≤ULN at the start of deferasirox treatment. In 37 patients with data available before and after dose increases to ≥30 mg/kg/day, no clinically relevant differences were observed in AE profile or laboratory parameters before and after dose increase. Deferasirox had no adverse effect on pediatric growth and adolescent sexual development. Overall, median SF levels in patients who received deferasirox treatment for ≥4 years decreased significantly from 3410 to 3108 ng/mL at end of study (median absolute change, –591 ng/mL, P=0.027; n=67). Decreases in SF were more pronounced when mean deferasirox dose increased to 〉20 mg/kg/day (Figure 1). In the deferasirox cohort, the median absolute change in SF levels from start of deferasirox to end-of-study was greater in patients aged ≥16 than 2–20 mg/kg/day, to achieve negative iron balance. Disclosures: Vichinsky: Novartis: Consultancy, Research Funding, Speakers Bureau; Apotex: Consultancy, Research Funding; Hemaquest: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bernaudin:Novartis: Investigator for SCD deferasirox (Exjade). Forni:Novartis: Research Funding. Gardner:Novartis: Research Funding. Hassell:Novartis: Research Funding. Heeney:Novartis: Research Funding. Kutlar:Novartis: Research Funding. Lane:Novartis: Research Funding. Mathias:Novartis: Research Funding. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Tebbi:Novartis: Speakers Bureau. Wilson:Novartis: Honoraria, Research Funding, Speakers Bureau. Griffel:Novartis: Employment. Deng:Novartis: Employment. Giannone:Novartis: Employment. Coates:Novartis: Research Funding, Speakers Bureau.
    Print ISSN: 0006-4971
    Digitale ISSN: 1528-0020
    Thema: Biologie , Medizin
    Publiziert von American Society of Hematology
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  • 4
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    Geographical Differences In Transfusion and Iron Chelation Practices In 1558 Patients with Transfusion-Dependent Anemias (2010)
    American Society of Hematology
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    Publikationsdatum: 2010-11-19
    Beschreibung: Abstract 4272 Background: Globally, a number of management guidelines provide recommendations for transfusion and iron chelation therapy across various transfusion-dependent anemias. Most treatment guidelines aim to control body iron burden by maintaining serum ferritin 2500 ng/mL across all anemias. Serum ferritin levels were ≥2500 ng/mL in 61.3% of patients across regions (50.6% [Europe], 59.3% [Middle East/Africa] and 74.3% [Asia-Pacific]). For patients with TM, TI, AA and SCD, serum ferritin levels were substantially higher in the Asia-Pacific region compared with other regions (Figure). In the Asia-Pacific region, the proportion of patients with serum ferritin levels ≥4000 ng/mL varied between 31.1% and 53.6% across anemias, compared with 14.3–37.5% in Europe. Conclusions: There are many differences in transfusion and iron chelation practices across regions, with most prominent differences in the Asia-Pacific region. Factors contributing to these differences might include regional variations in specific disease characteristics (severity, transfusion requirement), treatment practices (eg, hemoglobin level at which transfusion is initiated), the availability and accessibility of transfusion and iron chelation therapy including patients' compliance and physician attitude and adherence to treatment guidelines. The high proportion of patients with baseline serum ferritin 〉2500 ng/mL suggests that previous iron chelation regimens with DFO and/or deferiprone prior to the EPIC study were suboptimal with limitations for adequate control of iron burden across geographical regions. A greater improvement in iron chelation practices is warranted across the globe with an immediate focus on the Asia-Pacific region. Disclosures: Viprakasit: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gattermann:Novartis: Honoraria, Research Funding. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Taher:Novartis: Honoraria, Research Funding. Habr:Novartis: Employment. Roubert:Novartis: Employment. Domokos:Novartis: Employment. Cappellini:Novartis: Speakers Bureau.
    Print ISSN: 0006-4971
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    Thema: Biologie , Medizin
    Publiziert von American Society of Hematology
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    Probing the Origin of Chelatable Iron During Deferiprone and Combination Therapies: Insights From Plasma NTBI and LPI Determinations (2010)
    American Society of Hematology
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    Publikationsdatum: 2010-11-19
    Beschreibung: Abstract 5158 Objectives. Classic clinical and animal studies with deferoxamine (DFO) showed that two major chelatable pools exist in thalassemia major (TM), the first derived from hepatocytes and the second from red cell catabolism. Knowledge about the origin of chelatable iron with deferiprone (DFP) treatment, alone or when combined with DFO, is relatively limited. We hypothesized that changes in plasma iron species during chelation therapy may be proportional to the magnitude of chelatable iron pools. In this study, we have examined the relationship between urinary iron excretion (UIE), transfusional iron loading rates (ILR), liver iron concentration (LIC) and plasma concentrations of non-transferrin bound iron (NTBI) and labile plasma iron (LPI) before and after DFP therapies. Patients and methods. 12 TM patients were randomized to one year of DFP monotherapy (25mg/kg tds) or 9 to DFP at the same dose with the addition of subcutaneous DFO (40-50mg/kg), 2 nights a week (COMB). Plasma samples were taken for NTBI and LPI measurements, at baseline, at 1 week and at 52 weeks. These were obtained at 9am, which was 10hrs following the previous DFP dose, and 24h after the second of two weekly DFO doses for COMB patients. A 24h urine iron was collected at baseline, 1 week and 52 weeks of treatment. The ILR, expressed in mg/kg/day, was calculated from the blood volume transfused during the 1 year study. Results. After 1 week of treatment, there was a significant increase in NTBI from baseline in DFP and in COMB patients. A significant increase in LPI was also seen in DFP patients at this time (p=0.039). In all patients, absolute LPI levels at 1 week correlated with those of NTBI and increments in LPI also correlated with increments in NTBI from baseline to 1 week (r=0.52, p=0.002). Plasma NTBI levels at 1 week were proportional to UIE mg/kg/day)(r=0.51, p= 0.02), to LIC mg/g dry wt (r=0.54, p=0.01) and inversely proportional to the ILR (r=0.74, p=0.0001). By weighting the LIC and ILR pools equally, a combined chelatable pool index was derived: this was significantly proportional to both absolute NTBI at 1 week (r=0.72, p=0.003) and increments in NTBI from baseline. This index was also significantly correlated with UIE (p=0.66, p=0.0017) and with LPI at 1 week. Interpretation and conclusions. Urinary iron excretion with DFP (the predominant route of iron excretion with DFP) and COMB therapy is directly proportional to the LIC, as well as to plasma NTBI and LPI and is inversely proportional to the ILR. This is consistent with the existence of two major chelatable iron pools; the first being liver derived and the second derived from red cell catabolism. This latter pool appears to be larger for those patients who require less blood transfusion and who presumably have greater rates of ineffective eryrthropoiesis. The origin of chelatable iron with this form of COMB therapy, with DFO only two days a week, appears is similar to that of DFP monotherapy. Disclosures: Aydinok: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Deferiprone and desferrioxamine are indicated and approved for the chelation therapy of iron-overloaded patients with beta thalassemia. The combination of both agents as treatment regimen for patients with beta thalassemia is part of the investigation described in the abstract and is not approved for use. Manz:Lipomed AG: Employment. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.
    Print ISSN: 0006-4971
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    Thema: Biologie , Medizin
    Publiziert von American Society of Hematology
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    Efficacy of deferasirox in reducing and preventing cardiac iron overload in β-thalassemia (2010)
    American Society of Hematology
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    Publikationsdatum: 2010-03-25
    Beschreibung: Cardiac iron overload causes most deaths in β-thalassemia major. The efficacy of deferasirox in reducing or preventing cardiac iron overload was assessed in 192 patients with β-thalassemia in a 1-year prospective, multicenter study. The cardiac iron reduction arm (n = 114) included patients with magnetic resonance myocardial T2* from 5 to 20 ms (indicating cardiac siderosis), left ventricular ejection fraction (LVEF) of 56% or more, serum ferritin more than 2500 ng/mL, liver iron concentration more than 10 mg Fe/g dry weight, and more than 50 transfused blood units. The prevention arm (n = 78) included otherwise eligible patients whose myocardial T2* was 20 ms or more. The primary end point was the change in myocardial T2* at 1 year. In the cardiac iron reduction arm, the mean deferasirox dose was 32.6 mg/kg per day. Myocardial T2* (geometric mean ± coefficient of variation) improved from a baseline of 11.2 ms (± 40.5%) to 12.9 ms (± 49.5%) (+16%; P 〈 .001). LVEF (mean ± SD) was unchanged: 67.4 (± 5.7%) to 67.0 (± 6.0%) (−0.3%; P = .53). In the prevention arm, baseline myocardial T2* was unchanged from baseline of 32.0 ms (± 25.6%) to 32.5 ms (± 25.1%) (+2%; P = .57) and LVEF increased from baseline 67.7 (± 4.7%) to 69.6 (± 4.5%) (+1.8%; P 〈 .001). This prospective study shows that deferasirox is effective in removing and preventing myocardial iron accumulation. This study is registered at http://clinicaltrials.gov as NCT00171821.
    Print ISSN: 0006-4971
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    Prolongation of Progression Free Survival In Mantle Cell Lymphoma After RHCVAD: ASCT Consolidation or Rituximab Maintenance (2010)
    American Society of Hematology
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    Publikationsdatum: 2010-11-19
    Beschreibung: Abstract 3570 Mantle cell lymphoma (MCL) is a small B cell lymphoma, incurable with standard chemo-immunotherapy. The best initial treatment regimen remains unclear. Although it is generally acknowledged that aggressive approaches using combination chemotherapy and/or high dose chemotherapy can prolong survival, consensus on upfront treatment strategies for advanced MCL is currently lacking without randomized controlled data to guide treatment decisions. We conducted a retrospective cohort analysis to describe and compare the survival experiences of MCL patients at the University of Pennsylvania treated in the first-line setting with R-HCVAD (N=43) with or without autologous stem cell transplant (ASCT) or Rituximab maintenance. The primary study endpoints were PFS and OS as assessed by chart review and confirmed by SSDI database. Median follow up for all pts was 3 years. The median age was 53.7, and 76.7 % (n=33) were stage IV at diagnosis. 15 patients underwent consolidative ASCT. 11 pts received Rituximab maintenance. Comparing patients treated with R-HCVAD vs R-HCVAD + R maintenance vs. R-HCVAD + ASCT, there were no statistical differences in terms of age, ECOG PS, LDH, WBC, beta-2microglobulin, BM or GI involvement, bulky disease or blastoid variant at baseline. Median PFS for all patients was 3.9 years: R-HCVAD alone 2.1 years vs. R-HCVAD+R 3.9 years (P=0.02, HR 3.51, 95%CI: 1.2–10.2) vs R-HCVAD + SCT not reached (p=0.017, HR 3.7, 95%CI: 1.26–10.63). PFS survival rates at 2 years were 50%, 88% and 70%; 33%, 71/% and 63% respectively at 3 years, and 0%, 33% and 33 % at 5 years. 3 year OS for all patients was 84% (95% CI: 65–94) with no significant differences among the three approaches. Notably, only 1/8 patients treated with R-HCVAD + SCT relapsed after 2 years, with a median follow up of 4.8 years for these patients. Our data suggest a further improved PFS when R-HCVAD is consolidated with either Rituximab maintenance or ASCT. While neither of the two consolidative approaches appears superior in our limited data set, both show significant PFS prolongation when compared to R-HCVAD alone. Further prospective investigation of consolidative approaches after RHCVAD in a randomized fashion is warranted. Figure 1: Figure 1:. Disclosures: No relevant conflicts of interest to declare.
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    The Addition of Cyclosporine to Dasatinib Therapy of Murine Bcr-Abl+ Leukemia Improves Disease Control Independent of Altered Pharmacokinetics (2010)
    American Society of Hematology
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    Publikationsdatum: 2010-11-19
    Beschreibung: Abstract 600 Although therapy for Bcr-Abl+ leukemia has been revolutionized by the development of the tyrosine kinase inhibitors (TKI), some patients, particularly those with advanced phase chronic myeloid leukemia or acute lymphoblastic leukemia (ALL) have unsatisfactory responses. We have demonstrated that inhibition of calcineurin with cyclosporine (CsA) increases the sensitivity of Bcr-Abl cells to TKI; furthermore, combination therapy with CsA plus dasatinib cured all mice with Bcr-Abl+ ALL, whereas all of the mice treated with dasatinib alone died with leukemia (Gregory et al, Cancer Cell, 2010). While the synergistic effect is independent of MDR1 inhibition by CsA in vitro, the possibility remains that the demonstrated survival advantage of combination therapy is due to altered pharmacokinetics (PK)and increased dasatinib exposure. We sought to determine if co-administration of CsA with dasatinib alters dasatinib PK, if differences in PK are sufficient to explain differences in response to therapy in vivo, and if combination therapy appears to adversely affect T-cell numbers. Bl6 mice were treated with dasatinib (20mg/kg/d), cyclosporine (25mg/kg/d), or both by oral gavage. Serum from peripheral blood was obtained at 0, 1, 2, 4, 8, 12, 24, and 48 hours after single doses and after one week of therapy (trough, 1, 2, 4, 8, and 12 hours). Dasatinib levels were determined by LC/LC-MS/MS. Pharmacokinetic (PK) analyses indicate that after 1 week of therapy, co-administration of CsA with dasatinib increases the Cmax and AUCinf of dasatinib as compared to dasatinib alone (277.4 v. 107.7 ng/ml and 916.8 v 487.4 ng/ml*hr, respectively; Figure A). The PK profiles suggest that co-administration of CsA with dasatinib enhances enteric absorption of dasatinib, but has little effect on its systemic elimination. Next, Arf-/-Bcr-Abl+GFP+ leukemia cells (Williams et al, Genes Dev, 2007) were transferred into unirradiated recipients which were treated with dasatinib (10 or 20 mg/kg/d) or with combination therapy (CsA 25mg/kg/d with dasatinib 5 or 10 mg/kg/d) for 7 days. Leukemia bearing mice were euthanized and the bone marrow (BM), peripheral blood (PBL) and spleens (SPL) were assessed for leukemia burden by flow cytometry. Combined CsA and dasatinib results in better disease control, even at doses predicted to result in similar exposure to dasatinib alone (i.e. half). For example, the mean percentage of GFP+B220+ BM cells was 6.7% in mice treated with dasatinib 10mg/kg/d as compared to 0.1% in mice treated with dasatinib 5mg/kg/d plus CsA (p
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    Graft-Vs-Lymphoma (GVL) Induction with Allogeneic Hematopoietic Stem Cell Transplantation (SCT) for Primary Cutaneous T Cell Lymphomas (CTCL). (2010)
    American Society of Hematology
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    Publikationsdatum: 2010-11-19
    Beschreibung: Abstract 4574 Background CTCLs are generally incurable with conventional therapies. In particular, advanced mycosis fungoides (MF), Sézary syndrome (SS) and gamma delta varieties of CTCL have poor survival rates and are often refractory to traditional chemotherapy. Allogeneic SCT may provide a GVL effect and improve outcomes for these patients. Methods A retrospective analysis was performed at the University of Pennsylvania to identify all patients with CTCL who underwent allogeneic transplantation. 12 patients were identified who were transplanted between 2004 to 2010. A chart review was performed to obtain data about demographics, diagnosis, staging, treatment, transplantation and outcomes. Results Median age at diagnosis was 49 yrs and M:F ratio was 5:7. Prior to transplantation, 4 had MF (stages IIB, IIIB, IVA1, IVB; 2 with nodal transformation), 4 had SS (one stage IVA1, three IVA2; 1 with nodal transformation), and 3 had gamma delta T-cell lymphoma (all T3b). Median time from diagnosis to transplantation was 3.3 yrs (range 0.5@02b97 yrs). Patients had received a median of 8 non-chemotherapy, and 2 chemotherapy-based treatment modalities before being transplanted. Only 3 patients were in complete remission (CR) at the time of conditioning and 9 had evidence of active disease. Reduced intensity conditioning (RIC) was used in 10 cases (Flu/Bu, Flu/Cy or Flu/Mel), and conventional myeloablative conditioning (Cy/TBI) was used in 2. GVHD prophylaxis consisted of calcineurin inhibitor and methotrexate in all patients. The median follow up for all pts is 6.6 months (range 1.4 to 37.1 months) and 11.2 months for surviving patients. All patients engrafted with an ANC 〉500 a median 13 days after SCT. Median donor chimerism at day 100 after SCT in 10 evaluable pts was 97%. 7 of 12 patients developed acute GVHD, 4 of whom had grade 3 GVHD. Two patients died within the first 100 days, from sepsis with active disease. At day 100, 7 of 10 evaluable patients were in CR, with an additional patient achieving CR shortly after; therefore transplant induced and maintained CR in 6 pts with active disease. 3 patients relapsed after achieving CR a median of 11.4 months (range 5.3–13.0 months) after SCT. 2 patients never achieved CR, and progressed within a month of transplantation. The median PFS for all pts was 31 wks, and 1 yr and 2 yr PFS were 48% and 32% without an obvious plateau. 2 year OS was 53% (Figure 1). Median OS is not reached. 6 patients have died from progression (5) and GVHD (1), 5 remain in CR and 1 is alive with active disease. Conclusion RIC SCT can provide long-term disease control in patients with advanced CTCL otherwise refractory to immunotherapy and chemotherapy. Given the limited TRM, consideration for earlier transplant should be given. Larger retrospective and ideally prospective studies will further define the role of allogeneic SCT in this disease. Disclosures: Rook: Therakos: Speakers Bureau; HY Biopharma: Consultancy. Kim:TenX: Research Funding; Biocryst: Research Funding; Genmab: Research Funding; Glouchester: Research Funding; Celgene: Research Funding; Eisai: Consultancy.
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  • 10
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    Knockdown of HPRT Enables Selection of Genetically Modified Human Hematopoietic Progenitor Cells. (2010)
    American Society of Hematology
    Details
    Publikationsdatum: 2010-11-19
    Beschreibung: Abstract 3772 Genetic modification of autologous hematopoietic stem cells (HSC) has the potential for effective treatment of a wide variety of inherited blood disorders. However, HSC gene therapy has shown limited clinical efficacy (with notable exceptions), in part because of the small proportion of engrafted genetically corrected HSCs. The use of drug-resistance genes to enable selection for transduced HSCs has been explored, but with limited success. Previous studies from our laboratory have indicated that murine HSC can be selected with 6-Thioguanine (6TG), a relatively non-toxic drug used in the treatment of leukemias, after knocking down the expression of hypoxanthine-guanine phosphoribosyltransferase (HPRT), an enzyme that metabolizes 6TG to its active state. We sought to determine if these findings can be translated to human hematopoietic cells. In the present study, we transduced human myeloid (Molm13, MV4-11) and lymphoid cell lines (Reh) with lentiviral vectors expressing shRNA constructs targeting HPRT or a non-targeted control sequence (Ctrl). Two of the most promising constructs directed against HPRT (491 and 50) were studied in more detail to determine which is most effective. Cells were selected in puromycin and cell lysates analyzed for HPRT gene expression. Reverse-transcription, real-time PCR (RT qPCR) and western blotting demonstrated that construct 491 was most efficient in knocking down HPRT in human hematopoietic cell lines compared to construct 50 (and Ctrl). To determine whether knockdown of HPRT provided resistance to 6TG, cells were cultured in the absence or presence of different doses of 6TG and live cell concentrations were determined. While Ctrl transduced cells decreased in a dose dependent manner after 72h of 6TG treatment, cells transduced with constructs 491 and 50 were relatively resistant to 6TG. IC50 values for construct 491 were significantly higher (114μM for Molm13 and 46μM for Reh cell lines) than construct 50 (1μM for Molm13 and 10μM for Reh) in comparison to control transduced cells (0.4μM for Molm13 and 3.5μM for Reh). We assessed cell death in human hematopoietic cell lines by annexin V staining after exposure to 6TG at 48 and 72h. As expected, control transduced cells died of apoptosis upon 6TG treatment, while 491 and 50 transduced cells were resistant. Furthermore, 491 transduced cells were more resistant to apoptosis than 50 transduced cells. Based on these results, construct 491 was used to transduce human CD34+ progenitor cells isolated from umbilical cord blood along with control shRNA. Transduction efficiency varied from 25–35% as determined by %GFP expression by flow cytometry. Sorted GFP+ cells showed reduced expression of HPRT in 491 transduced cells compared to controls, as measured by RT qPCR. Similar to the effects in cell lines, in vitro proliferation of control transduced CD34+ cells diminished in response to increasing 6TG concentrations. There was an increase in the percentage of GFP+ cells in 6TG treated 491 transduced cells compared to untreated controls in a dose dependent fashion, indicating a selective advantage conferred to 491 transduced cells in the presence of 6TG. Importantly, 491 transduced cells continued to proliferate despite treatment with 6TG. Like 6TG, cisplatin requires mismatch repair (MMR) for cytotoxicity. To determine if HPRT knockdown had off-target effects impairing MMR, transduced cells were also treated with cisplatin. Both control and 491 transduced cells stopped proliferating in the presence of cisplatin indicating that MMR remained intact. These data indicate that human hematopoietic progenitor cells can be selected in vitro by knock-down of HPRT and treatment with 6TG. Xenografts of Ctrl and 491 transduced human CD34+ cord blood cells have been generated and are being treated with 6TG to determine if human cells can be selected with 6TG in vivo. Disclosures: Off Label Use: Off label use of 6-thioguanine will be suggested.
    Print ISSN: 0006-4971
    Digitale ISSN: 1528-0020
    Thema: Biologie , Medizin
    Publiziert von American Society of Hematology
    Standort Signatur Erwartet Verfügbarkeit
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